Abstract
Although, the suprachiasmatic nucleus (SCN) of the hypothalamus acts as the central clock in mammals, the circadian expression of clock genes has been demonstrated not only in the SCN, but also in peripheral tissues and brain regions outside the SCN. However, the physiological roles of extra-SCN circadian clocks in the brain remain largely elusive. In response, we generated Nkx2.1-Bmal1−/− mice in which Bmal1, an essential clock component, was genetically deleted specifically in the ventral forebrain, including the preoptic area, nucleus of the diagonal band, and most of the hypothalamus except the SCN. In these mice, as expected, PER2::LUC oscillation was drastically attenuated in the explants of mediobasal hypothalamus, whereas it was maintained in those of the SCN. Although, Nkx2.1-Bmal1−/− mice were rhythmic and nocturnal, they showed altered patterns of locomotor activity during the night in a 12:12-h light:dark cycle and during subjective night in constant darkness. Control mice were more active during the first half than the second half of the dark phase or subjective night, whereas Nkx2.1-Bmal1−/− mice showed the opposite pattern of locomotor activity. Temporal patterns of sleep-wakefulness and feeding also changed accordingly. Such results suggest that along with mechanisms in the SCN, local Bmal1–dependent clocks in the ventral forebrain are critical for generating precise temporal patterns of circadian behaviors.
Highlights
The circadian oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus is the central pacemaker in mammals, orchestrating multiple circadian rhythms in organisms (Reppert and Weaver, 2002; Dibner et al, 2010)
Prominent βGal expression was observed in the medial septum, nucleus of the diagonal band (Figure 1A), medial preoptic area (Figures 1B,G), and most areas of the hypothalamus: the ventromedial (VMH), dorsomedial (DMH), arcuate (Arc) (Figures 1D,J), mammillary nuclei (MN) (Figure 1E), and the lateral hypothalamic area (LHA) at the rostrocaudal level of and posterior to the VMH (Figure 1D)
We demonstrated that the SCN central clock alone cannot precisely delineate the locomotor activity pattern in the dark phase
Summary
The circadian oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus is the central pacemaker in mammals, orchestrating multiple circadian rhythms in organisms (Reppert and Weaver, 2002; Dibner et al, 2010). Each SCN cell has an individual cellular clock driven by autoregulatory transcriptional and translational feedback loops (TTFLs) of clock genes. Such cellular clocks appear in many peripheral tissues and brain regions outside the SCN (Balsalobre et al, 1998; Yamazaki et al, 2000; Yagita et al, 2001; Abe et al, 2002; Yoo et al, 2004; Guilding et al, 2009; Dibner et al, 2010). Knowledge of the physiological roles of brain clocks in extra-SCN regions remains limited (Roybal et al, 2007; Mukherjee et al, 2010; Mieda and Sakurai, 2011; Spencer et al, 2013; Yu et al, 2014; Nakano et al, 2016; Orozco-Solis et al, 2016; Shimizu et al, 2016).
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